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Diagnostic approach to the patient with

newly identified chronic kidney disease

Authors: Pedram Fatehi, MD, MPH, Chi-yuan Hsu, MD,

MSc
Section Editor: Gary C Curhan, MD, ScD
Deputy Editor: Shveta Motwani, MD, MMSc, FASN

Contributor Disclosures

All topics are updated as new evidence becomes available

and our peer review process is complete.

Literature review current through: Aug 2020. | This

topic last updated: Jun 10, 2020.

INTRODUCTION

Patients with kidney disease may have a variety

of clinical presentations. Some have symptoms
or signs that are directly referable to the kidney
(such as hematuria) or to associated extrarenal
manifestations (edema, hypertension, signs of
uremia). Many patients are asymptomatic and
are incidentally noted to have an elevated
serum creatinine, which may have been (or
upon further investigation is found to be) stable
for years.

This topic reviews the evaluation of patients with

newly identified chronic kidney disease (CKD).

The evaluation of patients who present with

subacute or acute kidney injury (AKI) is
discussed elsewhere:

● (See "Diagnostic approach to adult patients

with subacute kidney injury in an outpatient
setting".)

● (See "Evaluation of acute kidney injury

among hospitalized adult patients".)

The management of CKD patients is discussed

elsewhere:

● (See "Evaluation of acute kidney injury

among hospitalized adult patients".)

● (See "Overview of the management of

chronic kidney disease in adults".)

OVERVIEW

The evaluation of patients with an elevated

creatinine of any duration includes:

● Careful history and physical examination.

An important part of the history is the
duration of the increased creatinine and
any chronic exposures.

● Assessment of renal function by estimation

of the glomerular filtration rate (GFR).
Estimation of the GFR requires that patient
is in steady state. (See "Assessment of
kidney function".)

● Careful examination of the urine by both

qualitative chemical tests and microscopic
examination. The urinary findings narrow
the differential. (See "Urinalysis in the
diagnosis of kidney disease".)

● Radiographic imaging of the kidneys. (See

"Radiologic assessment of renal disease".)

● Serologic testing and tissue diagnosis with

renal biopsy if noninvasive evaluation is not
sufficient for diagnosis. (See "Glomerular
disease: Evaluation and differential
diagnosis in adults".)

Disease duration — The determination of

disease duration is an important aspect of the
evaluation. Making this determination accurately
requires the availability of older data for
comparison. Knowing the disease duration
helps to narrow the differential diagnosis of
cause and to provide prognostic information to
guide management.

The distinction between acute kidney injury

(AKI), subacute kidney injury, and CKD is
arbitrary, but the following definitions have been
established by consensus panels:

● Acute – AKI is defined by a rise in the

serum creatinine concentration or an
abnormal urine output that has developed
within hours to days. The criteria for AKI
include an increase in serum creatinine by
≥0.3 mg/dL (27 micromol/L) relative to a
known baseline value within 48 hours, or an
increase to ≥1.5 times the baseline value
within seven days, or a decrease in urine
volume to <3 mL/kg over six hours (Kidney
Disease: Improving Global Outcomes
[KDIGO]-AKI) (table 1).

AKI is most commonly diagnosed in

hospitalized patients. (See "Definition and
staging criteria of acute kidney injury in
adults".)

● Chronic – The National Kidney Foundation

Kidney Disease Outcomes Quality Initiative
(NKF-KDOQI) and the KDIGO CKD
guidelines define CKD as being present if
GFR <60 mL/min/1.73 m2 or evidence of
kidney damage such as albuminuria or
abnormal findings on renal imaging have
been present for three months or more.
(See "Definition and staging of chronic
kidney disease in adults", section on
'Definition of CKD'.)

● Subacute – KDIGO guidelines proposed

the term, acute kidney diseases and
disorders (AKD), to encompasses any
decrement in renal function occurring in
less than three months [1]. Disorders that
evolve over more than 48 hours but
generally in under three months are
informally referred to as subacute kidney
injury. There is considerable overlap in
acute and subacute presentations.

We emphasize that terminology is less

important than a clear understanding of the
natural history of such diseases. The
distinctions between subacute kidney injury and
CKD and between subacute kidney injury and
AKI can be arbitrary. As an example, a patient
who presents with an elevated creatinine over 6
to 12 months or who has an acute deterioration
of previously stable CKD is better evaluated as
subacute kidney injury rather than CKD. (See
"Diagnostic approach to adult patients with
subacute kidney injury in an outpatient setting",
section on 'Evaluation'.)

The assessment of disease duration is best

performed by comparing the current serum
creatinine concentration and/or urinalysis with
previous results. As an example, a patient with
a current serum creatinine concentration of 4
mg/dL (354 micromol/L) and a value of 0.6
mg/dL (53 micromol/L) one month previously
has acute or rapidly progressive disease. In
contrast, the same patient with a prior serum
creatinine concentration of 3.5 mg/dL (309
micromol/L) two years ago almost certainly has
slowly progressive CKD.

When a previous urinalysis, serum creatinine

concentration, and/or radiographic study are
unavailable, certain findings from the history
and physical examination may suggest the
duration of disease [2]. As examples:

● The recent onset of symptoms or signs,

such as sudden onset of anasarca and
discolored urine, suggests an acute
process.

● Marked oliguria (urine output <500 mL/day)

or anuria in a patient not on maintenance
dialysis indicates an acute process since
prolonged oliguria/anuria does not occur in
slowly progressive CKD (even if advanced).

● A progressive increase in the serum

creatinine concentration on a daily basis
after the initial evaluation indicates an acute
process while a stable value suggests
CKD.

● Imaging showing small kidneys provides

definitive evidence of chronicity. However,
the presence of normal-sized kidneys does
not exclude chronicity, since some causes
of CKD such as diabetic nephropathy are
associated with preserved kidney size.
Renal parenchyma echogenicity (normally
less echogenicity than of healthy liver
parenchyma), if markedly increased,
suggests nonspecific diffuse renal disease.
Increased echogenicity combined with
relatively small kidneys further supports
diagnosis of CKD [3-5]. (See "Radiologic
assessment of renal disease".)

● Radiologic evidence of renal

osteodystrophy such as subperiosteal bone
resorption or loss of bone density at the
distal third of the clavicles suggests CKD.
(See "Overview of chronic kidney disease-
mineral and bone disorder (CKD-MBD)".)

Other findings are less helpful. As an example,

anemia due to erythropoietin deficiency is a
common (though not absolute) finding in CKD,
but many acute diseases cause both hemolysis
or bleeding and AKI or subacute injury. Although
hyperphosphatemia commonly affects CKD
patients, it may also be seen in AKI or subacute
kidney injury, so it does not distinguish acute
from chronic disease. The lack of presence of
anemia or hyperphosphatemia does not exclude
the presence of CKD.

MAJOR CAUSES AND

CLASSIFICATION OF KIDNEY
DISEASE

The traditional approach to kidney disease has

been to categorize the clinical etiology as
prerenal (decreased renal perfusion pressure),
intrinsic renal (pathology of the vessels,
glomeruli, or tubules-interstitium), or postrenal
(obstructive). CKD may result from disease
processes in any of these categories.

Prerenal disease — Chronic prerenal disease

occurs in patients with ongoing heart failure or
cirrhosis with persistently decreased renal
perfusion, which increases the propensity for
intrinsic kidney injury, such as acute tubular
necrosis (ATN). Causes of acute or subacute
prerenal injury are discussed elsewhere. (See
"Diagnostic approach to adult patients with
subacute kidney injury in an outpatient setting",
section on 'Prerenal disease'.)

Intrinsic renal vascular disease — The most

common chronic renal vascular disease is
nephrosclerosis, which initially involves the
blood vessels but ultimately damages the
glomeruli and tubulointerstitium. (See "Clinical
features, diagnosis, and treatment of
hypertensive nephrosclerosis" and
"Hypertensive complications in black patients",
section on 'Risk of hypertensive complications'.)

Renal vascular diseases such as renal artery

stenosis from atherosclerosis or fibromuscular
dysplasia may, over the course of months or
years, cause ischemic nephropathy,
characterized by glomerulosclerosis and
tubulointerstitial fibrosis [6]. (See "Clinical
features, diagnosis, and treatment of
hypertensive nephrosclerosis" and "Clinical
manifestations and diagnosis of chronic kidney
disease resulting from atherosclerotic renal
artery stenosis" and "Clinical presentation,
evaluation, and treatment of renal
atheroemboli".)

Intrinsic glomerular disease — Chronic

glomerular disease may be classified as
nephritic or nephrotic.

● A nephritic pattern is suggested by an

abnormal urine microscopy with red blood
cell (RBC) casts and dysmorphic red cells,
occasionally white blood cells (WBCs), and
a variable degree of proteinuria [7,8]. (See
"Glomerular disease: Evaluation and
differential diagnosis in adults".)

● A nephrotic pattern is associated with

proteinuria, usually in the nephrotic range
(>3.5 g per 24 hours), and an inactive urine
microscopic analysis with few cells or casts.
(See "Glomerular disease: Evaluation and
differential diagnosis in adults".)

Some patients cannot be easily assigned to one

of these two categories.

Intrinsic tubular and interstitial

disease — The most common chronic
tubulointerstitial disease is polycystic kidney
disease (PKD). Other chronic etiologies include
nephrocalcinosis (most often due to
hypercalcemia and/or hypercalciuria),
sarcoidosis, Sjögren's syndrome, reflux
nephropathy in children and young adults, and
medullary cystic kidney disease in families with
a pattern of autosomal dominant inheritance.
(See "Autosomal dominant polycystic kidney
disease (ADPKD): Treatment" and
"Nephrocalcinosis" and "Kidney disease in
Sjögren's syndrome" and "Clinical presentation,
diagnosis, and course of primary vesicoureteral
reflux" and "Autosomal dominant
tubulointerstitial kidney disease (medullary
cystic kidney disease)" and "Renal disease in
sarcoidosis".)

There is increased recognition of relatively high

prevalence of CKD of unknown cause among
agricultural workers from Central America and
parts of Southeast Asia. (See "Mesoamerican
nephropathy".)

Subacute tubulointerstitial diseases are

discussed elsewhere. (See "Diagnostic
approach to adult patients with subacute kidney
injury in an outpatient setting", section on
'Intrinsic tubular and interstitial disease'.)

Postrenal (obstructive
nephropathy) — Chronic obstruction may be
due to prostatic disease or abdominal/pelvic
tumor with mass effect on ureter(s).
Retroperitoneal fibrosis is a rare cause of
chronic ureteral obstruction (see "Clinical
manifestations and diagnosis of retroperitoneal
fibrosis"). If untreated, obstructive nephropathy
leads to irreversible tubulointerstitial fibrosis (ie,
intrinsic disease). (See "Clinical manifestations
and diagnosis of urinary tract obstruction and
hydronephrosis".)

CLINICAL MANIFESTATIONS

CKD patients may present with symptoms and

signs resulting directly from diminished kidney
function. These include edema, hypertension,
and/or decreased urine output. However, many
patients have no clinical symptoms. In such
patients, kidney disease is detected by
laboratory tests that are obtained as part of an
evaluation of an unrelated disorder.

Depending on the duration and severity of CKD,

patients may also present with symptoms and/or
signs of prolonged renal failure, including
weakness and easy fatigability, anorexia,
vomiting, mental status changes, and seizures.

The total absence of urine (anuria) is never

observed with CKD or subacute kidney injury
alone and always indicates at least some
component of acute kidney injury (AKI).
However, anuria may be present among
patients with acute superimposed on chronic
kidney disease, such as is observed in a patient
with chronic obstruction who develops acute
urinary retention. Anuria occurs as a result of
severe/prolonged shock, bilateral urinary tract
obstruction, pregnancy-related cortical necrosis,
or bilateral renal arterial obstruction (eg,
dissecting aortic aneurysm). (See "Evaluation of
acute kidney injury among hospitalized adult
patients", section on 'Clinical manifestations'.)

The major laboratory findings in patients with

CKD include an increased serum creatinine
concentration and increased urea (blood urea
nitrogen [BUN]). Other common laboratory
abnormalities include anemia,
hyperphosphatemia, hyperkalemia, metabolic
acidosis, hypocalcemia, and elevated
parathyroid hormone (PTH) but not invariably.

The degree to which these abnormalities are

present depends on the severity of renal
dysfunction. Hyperphosphatemia is uncommon
among patients with estimated glomerular
filtration rate (eGFR) >45 mL/min/1.73 m2. PTH,
on the other hand, may be mildly elevated even
with a mild reduction of eGFR (ie, 50 to 60
mL/min/1.73 m2). (See "Overview of chronic
kidney disease-mineral and bone disorder
(CKD-MBD)", section on 'Overview'.)

A urinalysis may show albuminuria and/or an

abnormal urine microscopy. (See "Urinalysis in
the diagnosis of kidney disease".)

Radiographic findings (eg, multiple renal cysts

suggestive of polycystic kidney disease [PKD])
may be observed on imaging performed for
some other reason.

EVALUATION

The extent of the evaluation generally depends

on the severity and trajectory of creatinine
abnormality and on the results of urine tests and
renal imaging (often ultrasonography). Patients
with a glomerular filtration rate (GFR) that does
not change over sequential measurements,
minimal or no proteinuria, and no cellular
elements on urine microscopy undergo a limited
evaluation, and a renal biopsy is rarely
performed. In such patients, the cause of CKD
is usually not identified with certainty. By
contrast, patients with significant proteinuria and
glomerular hematuria or sterile pyuria often
undergo renal biopsy to determine cause, even
if the estimated GFR (eGFR) remains
unchanged. Abnormalities in renal imaging may
warrant urologic evaluation and urodynamic
studies. (See "Radiologic assessment of renal
disease".)

Among all patients, the medical history should

be carefully reviewed. Longstanding diabetes
and severe hypertension are common causes of
CKD. A history of severe peripheral vascular
disease and cardio- and cerebrovascular
disease may suggest renovascular disease.
(See "Clinical manifestations and diagnosis of
chronic kidney disease resulting from
atherosclerotic renal artery stenosis".)

A prior history of acute kidney injury (AKI),

particularly if severe (ie, dialysis requiring), may
suggest a cause of CKD (ie, in the absence of
other causes that may be revealed by history),
even if the patient describes sufficient recovery
to stop dialysis. (See "Kidney and patient
outcomes after acute kidney injury in adults",
section on 'Determinants of kidney outcomes'.)

A careful history may also reveal exposure to

lead, harsh physiological environments, or other
nephrotoxins. (See "Lead nephropathy and
lead-related nephrotoxicity" and "Balkan
endemic nephropathy" and "Nephropathy
induced by aristolochic acid (AA) containing
herbs" and "Cisplatin nephrotoxicity" and
"Chemotherapy nephrotoxicity and dose
modification in patients with kidney impairment:
Conventional cytotoxic agents" and
"Chemotherapy nephrotoxicity and dose
modification in patients with kidney impairment:
Molecularly targeted agents" and
"Mesoamerican nephropathy".)

Family history should be explored for familial

diseases such as polycystic kidney disease
(PKD), uromodulin kidney disease, or
glomerulonephritides such as C3
glomerulonephritis or immunoglobulin A (IgA)
nephropathy. (See "Autosomal dominant
tubulointerstitial kidney disease (medullary
cystic kidney disease)" and "C3
glomerulopathies: Dense deposit disease and
C3 glomerulonephritis", section on
'Pathogenesis' and "Pathogenesis of IgA
nephropathy", section on 'Genetic
predisposition' and "Autosomal dominant
polycystic kidney disease (ADPKD) in adults:
Epidemiology, clinical presentation, and
diagnosis".)

Medications should be carefully reviewed,

including historical medications. A history of
prolonged use of lithium, certain Chinese herbs,
or analgesic combination agents may suggest a
chronic interstitial lesion that caused CKD.

A constellation of symptoms and signs may

suggest a particular set of disorders. Edema,
heavy proteinuria, and little or no hematuria
suggest a nonproliferative glomerular disease
such as diabetic nephropathy.

Initial testing should include a serum creatinine

for the estimation of the GFR, reagent strip
urinalysis (dipstick) with urine microscopy, and
the quantification of urine protein or albumin (by
random or "spot" protein-to-creatinine ratio or
albumin-to-creatinine ratio) (algorithm 1). The
use of total protein versus albumin is debatable.
A more detailed discussion is presented
elsewhere (see "Assessment of urinary protein
excretion and evaluation of isolated non-
nephrotic proteinuria in adults"). Manual urine
microscopy for the assessment of urine
sediment is best performed by an experienced
operator.

We perform a renal ultrasound in all patients

with an increased serum creatinine of unclear
duration.

For patients who are at higher risk for multiple

myeloma, we obtain a serum protein
electrophoresis (SPEP) and urine protein
electrophoresis (UPEP), with immunofixation,
and a serum light chain assay at the time of the
initial evaluation. Patients who are considered at
higher risk for myeloma include all patients who
are >40 years of age who have a documented
increase in the serum creatinine within three to
six months and no other obvious cause for
increased creatinine, such as nonsteroidal
antiinflammatory drug (NSAID) use. Patients
who have other manifestations consistent with
myeloma are also considered at high risk
regardless of whether the creatinine increase is
documented to be within three to six months;
such manifestations include hypercalcemia,
bone pain, radiographic lesions, or anemia that
is disproportionate to CKD and otherwise
unexplained. In one retrospective study, testing
had a higher yield for paraprotein-related kidney
disease when CKD was more advanced on
presentation (ie, eGFR <45 mL/min/1.73 m2) or
when hypercalcemia (calcium >10.7 mg/dL) or
anemia (hemoglobin <10.6 g/L) was present [9].
(See "Kidney disease in multiple myeloma and
other monoclonal gammopathies: Etiology and
evaluation".)

The recognition of monoclonal gammopathy by

serum or urine electrophoresis or by abnormal
ratio of light chains in a patient with kidney
disease of uncertain etiology may prompt renal
biopsy for definitive diagnosis. Discussions of
monoclonal gammopathy of undetermined
significance (MGUS), myeloma, and
amyloidosis are presented elsewhere. (See
"Membranoproliferative glomerulonephritis:
Classification, clinical features, and diagnosis",
section on 'Monoclonal gammopathies' and
"Kidney disease in multiple myeloma and other
monoclonal gammopathies: Etiology and
evaluation" and "Renal amyloidosis".)

The results of the urinalysis and ultrasound

generally direct the remainder of the diagnostic
evaluation (algorithm 1).

Patients who have evidence of obstruction on

ultrasound may require further investigation and
intervention to relieve the obstruction and
determine the cause. (See "Clinical
manifestations and diagnosis of urinary tract
obstruction and hydronephrosis".)

Patients who have a urinalysis and/or albumin-

to-creatinine (or protein-to-creatinine) ratio that
suggests a glomerular or interstitial lesion
should be further evaluated based upon the
specific finding on urinalysis or based upon
determination of abnormal proteinuria. (See
"Urinalysis in the diagnosis of kidney disease"
and "Glomerular disease: Evaluation and
differential diagnosis in adults".)

Patients with sterile pyuria should be evaluated

for interstitial nephritis. (See "Clinical
manifestations and diagnosis of acute interstitial
nephritis", section on 'Diagnosis'.)

Patients who are high risk for renovascular

disease (hyperlipidemia, cigarette smoking, age
greater than 50 years, coronary artery disease